a. Field of Invention
The present invention relates to tripeptide derivatives with central nervous system activity, to a process for their preparation, and to intermediates therefor.
b. Description of the Prior Art
The main obstacle to the practical use of many biologically active peptides is their brief period of action which is partly due to their inactivation by proteolytic enzymes. An example of such a peptide is the tripeptide which is the factor inhibiting release of the melanocyte stimulating hormone (MIF or MRIH).
This tripeptide was isolated from bovine hypothalamic tissue by R.M.G. Nair et al., Biochem. Biophys. Res. Commun., 43, 1376 (1971) and its structure was established as the C-terminal tripeptide of oxytocin: H-L-prolyl-L-leucyl-glycinamide.
This tripeptide was shown to exert an action on the central nervous system (CNS). The tripeptide potentiates the behavioral effects of (3,4-dihydroxyphenyl)-L-alanine (L-DOPA) as shown by N. P. Plotnikoff et al., Life Sciences, 10, part 1, 1279 (1971) and E. Friedman et al., Science, 182, 831 (1973). The tripeptide antagonizes the effects of oxotremorine [N. P. Plotnikoff et al., Proc. Soc. Exp. Biol. Med., 140, 811 (1972)] and reverses the sedative effects of deserpidine in mice and monkeys [N. P. Plotnikoff et al., Neuroendocrinology, 11, 67 (1973)]. On the basis of the above biological activities A. V. Schally et al., Science 179,341 (1973) have suggested that the tripeptide H--Pro--Leu--Gly--NH.sub.2 could be useful in the treatment of patients suffering from depression or parkinsonism.
Since the elucidation of the structure of the above tripeptide, a limited number of analogs of this peptide have been synthesized by M. E. Celis et al., Febs Letters, 27, 327 (1972) and S. Castensson et al., Febs Letters, 44, 101 (1974). However, the natural tripeptide and the analogs known to date have the disadvantage of possessing a short duration of action due to rapid inactivation in the mammalian body and T. W. Redding et al., Neuroendocrinology, 11, 92 (1973) have demonstrated that the first step in the inactivation of the natural tripeptide appears to be proteolytic cleavage of the Pro-Leu bond with formation of proline and leucyl-glycinamide.
Accordingly, analogs of the natural tripeptide having a greater resistance to protease hydrolysis while retaining the CNS activity of the natural tripeptide are of interest. The present invention discloses novel analogs of the natural tripeptide in which the leucyl and glycyl amino acid residues may be replaced and the peptide linkage and the terminal amide may be substituted.
In addition, an unique and straightforward process for preparing these tripeptide derivatives is disclosed.